05 May 2014 RASML Officer OTC Medicines Evaluation Office of Medicines Authorisation Therapeutic Goods Administration PO Box 100 WODEN ACT 2606 Dear Sir/Madam, Re: OTC nasal decongestant preparations for topical use - proposed advisory statements for labelling Novartis Consumer Health (NCH) is the manufacturer and distributor of Otrivin® containing xylometazoline hydrochloride as the active ingredient. We appreciate the opportunity to respond to the consultation on the proposed advisory statements for OTC nasal decongestant preparations for topical use. Our comments on the proposed Required Advisory Statements for Medicine Labels (RASML) are discussed below. 1. Proposed advisory statement: "Frequent or prolonged use may cause nasal congestion to recur or worsen." NCH supports this advisory statement, as it provides clear information for consumers on why the medicine should not be used more frequently or longer than directed. 2. Proposed advisory statement: "Do not use for more than three days at a time unless advised by a doctor or pharmacist." NCH proposes to amend this statement to "Do not use for more than three five days at a time unless advised by a doctor or pharmacist." We agree that consumers need clear instructions on the maximum duration of use. However, the recommendation for 3 days is inconsistent with the body of clinical evidence and Australian standard reference texts. Clinical evidence Topical nasal decongestants are widely used to alleviate symptoms of rhinitis. These products are very effective at rapidly improving nasal congestion1, a symptom which may in turn cause insomnia, snoring and disturbed sleep1,2. Current evidence suggests prolonged or repeated use of topical decongestants can cause problems, leading to the development of rhinitis medicamentosa (RM), commonly known as rebound congestion. This phenomenon becomes more frequent the longer the decongestant is used1,3,4,5,6. It’s understandable that when this occurs, patients become uncertain as to whether congestion is still being caused by the nasal disease or by RM. For this reason NCH agrees that there should be a statement on the packaging giving consumers clear instructions on the maximum duration of use. However, the timeframe of 3 days is inconsistent with the body of clinical evidence, and the mean duration of nasal symptoms experienced throughout the common cold; four to five days7,8,9. The rebound effect of topical decongestants has only been described experimentally in healthy subjects10,11,12,13. Despite the fact that there are a similar number of studies in healthy subjects that failed to demonstrate any rebound effect14,15,16,17, the results from these studies cannot be directly extrapolated to patients with rhinosinusitis. The nasal mucosa of healthy subjects is not subjected to the cytokine environment associated with inflammation. The inflamed nasal mucosa treated with a topical decongestant does not present the same absorption properties as healthy nasal mucosa1. Evaluation of the congestion possibly induced by a topical nasal decongestant is consequently biased. Randomised controlled trials conducted in subjects with inflammation of the nasal mucosa, show no signs of RM after treatment times of up to ten days. This is shown for studies conducted with xylometazoline18,19,20,21 and oxymetazoline22,23. Subsequently, the majority of clinical reviews recommend limiting treatment time to ten days2,3,6,11,24, with some cautiously recommending up to 7 days5,25,26,27. Only one review had their lower limit of recommendation as 3 days5. The justification was not based on evidence but on the assumption that if a consumer was to choose to use it for longer, they still will be within a safe limit of use. However, supporting this rationale could encourage consumers to take a relaxed approach to medication labelling once they become aware directions for use can be extended. Australian standard reference texts Australian healthcare professionals frequently refer to the Therapeutic Guidelines, Australian Medicines Handbook (AMH), PSA's Non-prescription Medicines in the Pharmacy and Australian Pharmaceutical Formulary and Handbook (APF). In particular, the AMH and APF are standard texts required to be kept in pharmacies as per the Pharmacy Board practice standards and these are the references used by the majority of practicing pharmacists. NCH notes that all the above references recommend a treatment duration of no more than 5 days, due to the risk of rebound congestion: Australian Therapeutic Guidelines28: “maximum of 5 days” for oxymetazoline, tramazoline and xylometazoline. AMH29: “Do not use this medicine more than recommended or for more than 5 days at a time as it can worsen your symptoms when you stop using it.” PSA’s Non-Prescription Medicines in the Pharmacy30: “Nasal decongestants should not be used for longer than 5 days at a time.” APF31: “Topical decongestants should not be used for more than 5 days: prolonged use causes rebound congestion.” NCH believes that the proposed advisory statements should be aligned with the standard reference texts used by Australian healthcare professionals. References 1. Mortuaire G, de Gabory L, François M, Massé G, Bloch F, Brion N, Jankowski R, Serrano E. Rebound congestion and rhinitis medicamentosa: nasal decongestants in clinical practice. Critical review of the literature by a medical panel. Eur Ann Otorhinolaryngol Head Neck Dis. 2013 Jun;130(3):137-44. 2. Graf P. Rhinitis medicamentosa: a review of causes and treatment. Treat Respir Med. 2005;4(1):21- 9. 3. Graf P. Rhinitis medicamentosa. Clin Allergy Immunol. 2007;19:295-304. 4. Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J Investig Allergol Clin Immunol. 2006;16(3):148-55. 5. Rudy SF. Preventing and treating rhinitis medicamentosa. Nurse Pract. 1997 Nov;22(11):13, 115-6. 6. Passàli D, Salerni L, Passàli GC, Passàli FM, Bellussi L. Nasal decongestants in the treatment of chronic nasal obstruction: efficacy and safety of use. Expert Opin Drug Saf. 2006 Nov;5(6):783-90. 7. Turner R. Epidemiology, pathogenesis, and treatment of the common cold. Ann Allergy Asthma Immunol 1997;78:531– 40. 8. Heikkinen T, Järvinen A. The common cold. Lancet 2003; 361: 51–59. 9. De Sutter AIM, van Driel ML, Kumar AA, Lesslar O, Skrt A. Oral antihistamine-decongestant- analgesic combinations for the common cold. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD004976. 10. Morris S, Eccles R, Martez SJ, et al. An evaluation of nasal response following different treatment regimes of oxymetazoline with references to rebound congestion. Am J Rhinol 1997;11:109—15. 11. Akerlund A, Bende M. Sustained use of xylometazoline nose drops aggravates vasomotor rhinitis. Am J Rhinol 1991;5:157—60. 12. Graf P. Long-term use of oxy- and xylometazoline nasal sprays induces rebound swelling, tolerance, and nasal hyperreactivity. Rhinology 1996;34:9—13. 13. Vaidyanathan S, Williamson P, Clearie K, et al. Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion. Am J Respir Crit Care Med 2010;182:19—24. 14. Yoo JK, Seikaly H, Calhoun KH. Extended use of topical nasal decongestants. Laryngoscope 1997;107:40—3. 15. Watanabe H, Foo TH, Djazeri B. Oxymetazoline nasal spray three times daily for four weeks in normal subjects is not associated with rebound congestion or tachyphylaxis. Rhinology 2003;41:167—74. 16. Petruson B, Hansson HA. Function and structure of the nasal mucosa after 6 weeks use of nose drops. Acta Otolaryngol (Stockh) 1982;94:563—9 17. Petruson B. Treatment with xylometazoline (Otrivin) nosedrops over a six-week period. Rhinology. 1981; 19:167-72. 18. Eccles, R., Eriksson, M., Garreffa, S., and Chen, S.C., The nasal decongestant effect of xylometazoline in the common cold, Am J Rhinol 22, 1–22, 2008 19. Eccles, R., Pedersen, A., Regberg, D., Tulento, H., Borum, P., Stjärne, P. Efficacy and safety of topical combinations of ipratropium and xylometazoline for the treatment of symptoms of runny nose and nasal congestion associated with acute upper respiratory tract infection. Am J Rhinol. 2007 Jan-Feb;21(1):40-5 20. Graf, P., Juto, J.-E., Sustained use of xylometazoline nasal spray shortens the decongestive response and induces rebound swelling. Rhinology, 33, 14-17, 1995 21. Strandell, B., Norgren-Holst, E., Tran, N., Jakobsen, H.B., and Chen, S. OTC use of a topical nasal spray solution containing xylometazoline plus ipratropium in patients with common cold. International Journal of Clinical Pharmacology and Therapeutics, Vol. 47 – No. 12/2009 (744-751) 22. Graf, P., Enerdal, J., Hallén, H. Ten days' use of oxymetazoline nasal spray with or without benzalkonium chloride in patients with vasomotor rhinitis. Arch Otolaryngol Head Neck Surg. 1999 Oct;125 (10):1128-32. 23. Morris, S., Eccles, R., Martez, S.J., Riker, D.K., Witek, T.J. An evaluation of nasal response following different treatment regimes of oxymetazoline with reference to rebound congestion. Am J Rhinol. 1997 Mar-Apr;11 (2):109-15. 24. Graf, P.and Juto J. Correlation between objective nasal mucosal swelling and estimated stuffiness during long-term use of vasoconstrictors. ORL 1994;56:334-339 25. Archontaki M1, Symvoulakis EK, Hajiioannou JK, Stamou AK, Kastrinakis S, Bizaki AJ, Kyrmizakis DE. Increased frequency of rhinitis medicamentosa due to media advertising for nasal topical decongestants. B-ENT. 2009;5(3):159-62. 26. Black MJ, Remsen KA. Rhinitis medicamentosa. Can Med Assoc J. 1980 Apr 19;122(8):881-4. 27. Stübner UP1, Toth J, Marks B, Berger UE, Burtin B, Horak F. Efficacy and safety of an oral formulation of cetirizine and prolonged-release pseudoephedrine versus xylometazoline nasal spray in nasal congestion. Arzneimittelforschung. 2001 Nov;51(11):904-10. 28. eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited; 2013 Mar. Accessed 2013 April 15 http://online.tg.org.au/complete/desktop/index.htm. 29. Australian Medicines Handbook 2014 (online). Adelaide: Australian Medicines Handbook Pty Ltd; 2014 January.